1. Introduction
Most of the efforts currently under way to discover new therapeutic drugs for disorders of the central nervous system (CNS) will also face the problem of delivering them to the brain without impairing the activity or integrity of such substances or compounds, while minimizing systemic adverse effects. And that means finding a way around—or through—the blood brain barrier (BBB), a physiological barrier between bloodstream and brain.
A National Institutes of Mental Health (NIMH) study showed that, in the United States, one out of three individuals suffers from a CNS disorder at some time in life. Approximately two million in the same country have suffered a stroke, which is the third leading cause of death in the United States.
2. Iontophoresis
After the discovery of the electrical nature of nerve impulse by Galvani in 1791, attention focused on the possibility of using electricity as a mode of drug delivery. It has been long known that medicines could be introduced into the human body by way of the skin. The skin has a selective permeability to lipophilic (lipid soluble) substances and acts as a barrier to hydrophilic (water soluble) substances. In 1747, Veratti suggested that hydrophobic drugs might be Introduced to the subcutaneous tissue through human skin by the application of a direct current. This mode has become known as iontophoresis (meaning ion transfer).
In Table 1 we present several examples of drugs introduced through the skin by iontophoresis for some conditions.
TABLE 1Drugs introduced by iontophoresis for corresponding conditions.substances that can be introduced by iontophoresisDrugConditionAcetic acidMyositis ossificansAspirinRheumatic diseasesDexamethasone and lidocaineTendinitis, bursitis,rheumatoid arthritisDiclofenac sodiumScapula-humoralperiarthritis, elbowepicondylitisIodineFibrosis, adhesions,scar tissue, triggerfingerlidocainelocal anesthesiaMorphinePost-operative analgesiaPilocarpineSweat test (cysticfibrosis)PirpropheneRheumatic diseasesPotassium citrateRheumatoid arthritisPotassium iodideScar tissueSilverChronic osteomyelitisSalicylatePlantar warts, scar tissueSodium fluorideTooth hypersensitivity
This is only a small part of different drugs or biologically active substances that can be introduced by iontophoresis. Many lipophilic drugs, such as scopolamine for motion sickness, clonidine for hypertension, and nitroglycerin for the treatment of angina pectoris, can be readily delivered through human skin. With these drugs, the concentration gradient between the drug-loaded reservoir and the body is sufficient enough to deliver the drug through the skin at therapeutic dosage rates. However, this is not the case for hydrophilic drugs.
Because topical application fails to deliver therapeutic dosages of hydrophilic drugs, traditional methods, such as oral or parenteral systemic drug administration, have been favored. However, these methods have several disadvantages.
First, systemic administration may lead to massive inactivation of a drug as a result of the enzymatic action of the liver. Also, oral administration may give rise to incomplete or erratic absorption due to factors like food interaction, inactivation in the gastro-intestinal tract, disease status, and concomitant medication. Furthermore, oral drug administration may give rise to fluctuations in the concentration of a drug in the systemic circulation. This may in turn result in toxic or sub-therapeutic blood levels of the drug.
These problems have been and still are the subject of extensive research and can only partly be dealt with in most cases using different methods including oral administration of pro-drugs and controlled release dosage forms. However, these problems may also be avoided by the use of iontophoresis. Using electric current as an external driving force, hydrophilic, charged drugs can be readily introduced through the epidermal level.
Various types of drugs are potential candidates for iontophoresis. Hydrophilic, charged drugs with relatively low molecular weight are the most suitable for the procedure, although the delivery of some large peptides and hormones by this technique has also proven to be successful.
Direct current, or galvanic current, is the current of choice for iontophoresis. Direct current allows the maximum ion transfer per unit of applied current, because its course is uninterrupted.
According to ohm's law: V=IR,
where V is voltage, I is current, and R is resistance, the voltage generated within the system is therefore dependent on the resistance of the skin or other tissue during the treatment.
It has been suggested by many investigators that penetration of hydrophilic, charged substances occurs mainly by way of sweat ducts, sebaceous glands, and hair follicles and imperfection of the skin (The Shunt Pathway theory).
According to the flip-flop gate mechanism, it has been suggested that permeability of skin may be altered as a result of the application of an electric potential across the skin. Jung et al. in 1983 found that the only structural requirement for pore formation was the presence of alpha-helical polypeptides. When an electric potential is applied across a physiological membrane, a voltage-dependent “flip-flop,” of the helices occurs. The skin permeability can be enhanced by the formation of “artificial shunts” by the use of direct current as applied during iontophoresis.
The following factors affect iontophoretic skin permeation:
▪—molecular weight,
▪—current density,
▪—skin impedance,
▪—ion conductivity,
▪—pH of the drug solution,
▪—ion valence,
▪—duration of iontophoresis,
▪—concentration of the drug ion in the solution.
In optimal conditions, an organism receives only 10% of the substance on the electrode applied to the skin. In fact, an organism may receive from 1 to 10% of the substance.
Therapeutically, a current density of less than 1 mA per square inch of electrode surface is recommended.
According to Faraday's, First Law of Electrolysis, which states that the mass of a substance liberated at (or dissolved from) an electrode during electrolysis is directly proportional to the quantity of electrolyte.
An electrolyte can be defined as a substance that conducts electric current as a result of dissociation into positively and negatively charged particles called ions, which migrate toward and ordinarily are discharged at the negative and positive electrodes (cathode and anode respectively), of an electric circuit. The most familiar electrolytes are acids, bases, and salts, which ionize when dissolved in such polar solvents as water or alcohol. An essential requirement for solvents to be used is that they conduct electric current and have to possess an electric dipole.
Polar solvents consist of strong dipolar molecules having hydrogen bonding. Water is a very unique polar solvent in that it also has a high dielectric constant, which indicates the effect that a substance has, when it acts as a medium, on the ease with which two oppositely charged ions may be separated. The higher the dielectric constant of a medium, the easier it is to separate two oppositely charged species in that medium, which is an essential requirement for the existence of ionized molecules that may be moved by an electric current, as with iontophoresis.
Table 2 shows some useful polar solvents with their dielectric constants. The values listed are relative to a vacuum which by definition has a dielectric constant of unity.
SolventDielectric constant (ε at 20° C.)water80glycerin46ethylene glycol41methyl alcohol33ethyl alcohol25n-propyl alcohol22
The degree of dissolution and subsequent ionization can be improved and regulated by means of the addition of suitable electrolytes forming buffer systems in the selected polar solvent or mixtures thereof.
Siddiqui et al. found that during passive absorption the penetration rate of lidocaine was greatest at the higher pH levels (9.4 and 11.7), where lidocaine is mainly non ionized. On the other hand, lidocaine is mainly in the ionized form at pH 3.4 and 5.2.
During transdermal iontophoresis, drugs do not penetrate to a big depth. After applying a current of 5 mA to the right side and 0 mA to the left side for 20 minutes, radiolabeled Dexamethasone was detected to a maximal depth of 1.7 cm in the right side, which was the location of the hip joint capsule of the monkey (Glass et al).
For electrophoresis, not only direct (galvanic) current can be used, but other different impulse currents as well of both direct polarity and alternating polarity in a rectified regime (diadinamic, sinusoidal, fluctuating, etc.).
It is possible to use or to combine different types of energy. For example, we can combine iontophoresis with ultrasound, magnetic field, temperature-increase, etc.
When choosing a polarity, it is necessary to take into account that ions of all the metals, local anesthetic drugs, most alkaloids, and antibiotics have all a positive charge at physiological pH. Therefore, they must be introduced from an anode. On the other hand, ions of all the metalloids and acid radicals have all a negative charge at a physiological pH, and must be introduced from a cathode. There have been a series of interesting results proving a successful local introduction of drugs and other chemical substances into animal brains by means of micro-iontophoresis.
3. Pharmacokinetics
3.1 Physicochemical Factors in Transfer of Drugs Across Membranes.
The absorption, distribution, biotransformation, and excretion of a drug all involve its passage across cell membranes. Important characteristics of a drug are its molecular size and shape degree of ionization, and relative lipid solubility of its ionized and non ionized forms.
Passive Processes
Drugs cross membranes by either passive processes or by mechanisms involving the participation of components of the membrane. Both non-polar lipid-soluble compounds and polar water-soluble substances that retain sufficient lipid solubility can cross the lipid portion of the membrane by passive diffusion. Such transfer is directly proportional to the concentration gradient across the membrane. The greater the partition coefficient, the higher the concentration of drug in the membrane and the faster is its diffusion. Bulk flow of water carries with it any water-soluble molecule that is small enough to pass through the channels. Filtration is a common mechanism for transfer of many small, water-soluble, polar and non-polar substances.
Capillary endothelial cells have large channels (40 Å) and molecules as large as albumin may pass to a limited extent from the plasma to the extracellular fluid. In contrast, the channels in the intestinal epithelium and most cell membranes are about 4 Å in diameter and permit passage only of water, urea, and other small, water-soluble molecules. Substances generally do not pass through channels in cell membranes if their molecular mass is greater than 100 to 200. Most inorganic ions are sufficiently small to penetrate the channels in membranes, but their concentration gradient across the cell membrane is generally determined by the transmembrane potential.
Weak Acids and Bases and Influence of pH.
Most drugs are weak acids or bases and are present in solution as both the non-ionized and ionized species. The non-ionized portion is usually lipid soluble and can readily diffuse across the cell membrane. In contrast, the ionized fraction is often unable to penetrate the lipoid membrane because of its low lipid solubility, or to pass the membrane channels because of its size. If the ionized portion of a weak electrolyte can pass through the channels, or through the membrane, it will distribute according to the transmembrane potential in the same manner as an inorganic ion.
Carrier-Mediated Active Membrane Transport.
Passive processes do not explain the passage of all drugs across cell membranes. Active transport is responsible for the rapid transfer of many organic acids and bases across the renal tubule, choroid plexus, and hepatic cells. The transported substance is transferred against an electrochemical gradient.
Transcellular fluxes are formed by the active transport of Na+ across epithelial cells. Proteins and other macromolecules slowly cross epithelial cells by pinocytosis, a form of vesicular transport.
3.2 Absorption of Drugs
It is of practical importance to know the manner in which drugs are absorbed. The rate of absorption influences the time course of drug effect, and it is an important factor in determining drug dosage. In addition, choice of the route by which a drug is administered is often influenced by considerations of drug absorption.
Factors that Modify Absorption.
Absorption from all sites of administration is dependent upon drug solubility. Drugs given in aqueous solution are more rapidly absorbed than those given in oily solution, suspension, or solid form. For those given in solid form, the rate of dissolution may be the limiting factor in their absorption. Local conditions at the site of absorption alter solubility. The concentration of a drug influences its rate of absorption.
Drugs ingested or injected in solutions of high concentration are absorbed more rapidly than are drugs in solutions of low concentration. The circulation to the site of absorption also affects drug absorption. Increased blood flow, brought about by massage or local application of heat, enhances absorption of a drug. The area of the absorbing surface to which a drug is exposed is one of the more important determinants of the rate of drug absorption. Often there is a choice of the route by which a therapeutic agent may be given, and a knowledge of the advantages and disadvantages of the different routes of administration is then of primary importance. Oral ingestion is the most ancient method of drug administration. Disadvantages to the oral route include emesis as a result of irritation to the gastrointestinal mucosa, destruction of some drugs by digestive enzymes or low gastric pH, and formation of complexes with food components that cannot be absorbed. Drugs absorbed from the gastrointestinal tract may be extensively metabolized by the liver before they gain access to the general circulation. The parenteral injection of drugs has certain distinct advantages over oral administration. In some instances, parenteral administration is essential for the drug to be absorbed in its active form. Absorption is usually more rapid and more predictable than when a drug is given by mouth. Injection of drugs also has its disadvantages. Strict asepsis must be maintained to avoid infection, an intravascular injection may occur when it is not intended, pain may accompany the injection, and it is often difficult for a patient to perform the injection himself. Parenteral therapy is also more expensive and less safe than oral medication.
Intrathecal Administration
The blood-brain barrier and the blood-cerebrospinal fluid barrier often preclude or slow the entrance of drugs into the CNS. Therefore, when local and rapid effects of drugs on the meninges or cerebrospinal axis are desired, as in spinal anesthesia or acute CNS infections, drugs are sometimes injected directly into the spinal subarachnoid space.
4. The Blood-Brain Barrier
It has long been known that the bulk of the brain and the spinal cord is surrounded by a specially secreted clear fluid called the cerebrospinal fluid (CSF). Chemical substances such as metabolites move relatively freely from the alimentary canal into the blood, but not into the CSF. As a result, the blood levels of sugars, amino acids or fatty acids fluctuate over wide range while their concentrations in the CSF remain relatively stable. The same is true for hormones, antibodies, certain electrolytes, and a variety of drugs. Injected directly into the blood they act rapidly on peripheral tissues such as the muscles, heart, or glands but they have little or no effect on the central nervous system (CNS).
When administered into the CSF, however, the same substances exert a prompt and strong action. The conclusion is that the substances injected into the blood do not reach the CSF and the brain with sufficient rapidity and in an effective concentration.
The way in which the brain keeps its environment constant is frequently discussed in terms of a blood-brain barrier (BBB). Once substances have found their way into the CSF, they are free to diffuse into the tissues of the brain. The entry of hydrophilic and relatively large molecules into the CNS is restricted by the existence of a BBB. The BBB separates the brain from the blood circulation and is involved in the homeostasis of the brain. The BBB is situated in the brain microvessels and is composed of various cell types like endothelial cells, astrocytes, microglial cells, perivascular macrophages, and pericytes. The cerebral and endothelial cells form the morphological and functional basis of the BBB.
5. Nasal Cavity and Olfactory Region
Internal Nose
On each side of the nose are anterior and posterior openings called the nares. The posterior nares are also called the choanae. The vestibule is the anterior, skin-lined part of the nasal cavity. The nasal septum divides the nose into the two fossae. The lateral wall of the nose is a complicated area anatomically. There are four nasal turbinates, or conchae. Named from below upward, they are the inferior, middle, superior and supreme turbinates. The mucous membrane of the inferior turbinate is very rich in blood vessels and is semi-erectile. The several nasal meatuses are named according to the turbinates that overlie them.
Above the superior and supreme turbinates is the sphenoethmoidal recess, into which the sphenoidal sinus opens. Under the mucosa of the lateral wall of the inferior meatus are large blood vessels (sphenopalatine branches).
Both the external and the internal carotid systems provide a blood supply to the nose. The venous drainage is important because part of it, through the angular vein, leads to the inferior ophthalmic vein and eventually to the cavernous sinus. Most of the venous drainage, however is downward through the anterior facial vein.
Lymphatic drainage of the nose is extensive and parallels the venous drainage.
The olfactory area is located high in the nasal vault above the superior turbinate. Sensory hairs extend from the surface of the olfactory area to the cells that lie deep in the mucosa.
Nerve fibers subserving the sense of smell have their cells of origin in the mucous membrane of the upper and posterior parts of the nasal cavity. The entire olfactory mucosa covers an area of about 2.5 cm2. The central processes of olfactory fila are very fine unmyelinated fibers that converge to form small fascicles enwrapped by Schwann cells and pass through openings in the cribriform plate of the ethmoid bone into the olfactory bulb. The axons of the mitral and tufted enter the olfactory tract, which courses along the olfactory groove of the cribriform plate to the cerebrum. Some fibers project to the medial dorsal nucleus of the thalamus and the hypothalamus. That olfactory stimuli and emotional stimuli are strongly linked is not surprising, in view of their common roots in the limbic system.
According to Bell, the olfactory system has direct neuroanatomical and neurophysiological input to the amygdala and eventually hippocampus. Therefore it is conceivable that chemical stimuli at low levels could trigger limbic dysfunction in patients who happen to meet descriptive criteria for somatization disorder. It is also stated that there is no blood-brain barrier in the nasal passages. The limbic structure (e.g. the amygdala, olfactory bulb and hippocampus) can become easily kindled. The olfactory nerves can transport toxins directly to the limbic system. This may result in symptoms including memory loss, irritable bowel, and migraine headaches.
It has been suggested by Shipley, that it is possible to transport substances which come into contact with the nasal epithelium to the brain and that it is thus possible to influence the function of neurons in the brain, including some which have extensive projection to wide areas of the CNS.
6. The Optic Nerve
The optic nerve, mediating vision, is distributed to the eyeball. Most of its fibers are afferent and originate in the nerve cells of the ganglionic layer of the retina. Developmentally, the optic nerves and the retinae are parts of the brain and their fibers with glia.
The optic nerve, about 4 cm long, is directed backwards and medially through the posterior part of the orbital cavity. It then runs through the optic canal into cranial cavity and joins the optic chiasma. The optic nerve is enclosed in three sheaths, which are continuous with the membranes of the brain, and are prolonged as far as the back of the eyeball. Therefore, there is a direct connection between the optic nerve and the brain structures.
Itaya and van Hoesen described transneuronal retrograde labeling of neurons in the stratum griseum superficiale of the superior colliculus following intraocular injection of wheat germ agglutinin-horseradish peroxidase. A study of the distribution of wheat germ agglutinin-horseradish peroxidase in the visual system following intraocular injections in the chick, rat and monkey confirmed early findings of transneural transport of this conjugate in vivo.
From the overview of the literature given above we can conclude the following. Many substances such as metabolic products, drugs, and other substances cannot or only to a limited extent cross the BBB from the blood into the brain. From the nasal cavity these substances can penetrate into the brain because in the area of 2.5 cm2 of the upper posterior part of the nasal cavity, the BBB does not exist. Therefore, substances introduced into the upper part of the nasal cavity can directly enter the brain. Access to the CNS is also possible through the optic nerve.